Certain aminoalkyl phenylcarbamates are selective acetylcholine esterase inhibitors and are therefore potentially useful as pharmaceuticals for the treatment of brain disorders such as dementia, Alzheimer's disease, Huntington's chorea, tardive dyskinesias, confusion disorders and ataxia. One such compound, the hydrogen tartrate salt of (S)-ethylmethylcarbamic acid 3-[1-(dimethylamino)ethyl]phenyl ester (Rivastigmine, 1), is marketed as a pharmaceutical for the treatment of dementia of the Alzheimer's type.

Processes for the preparation of these types of aminoalkyl phenylcarbamates are described in patents U.S. Pat. No. 4,948,807, EP 193926, U.S. Pat. No. 5,602,176, GB 2409453, CN 1486973 and WO 04/037771. These patents disclose the preparation of phenyl carbamate compounds involving reaction of phenol compounds with appropriate isocyanates or carbamoyl halides. The process using isocyanates employs benzene as a solvent. Moreover, isocyanates such as lower alkyl isocyanates are hazardous to handle due to their toxic and volatile nature. Another reported alternative process uses carbamoyl halides along with reactive bases like sodium hydride, to prepare the carbamates. The carbamoyl halides are carcinogenic substances and are not easy to handle on an industrial scale. Moreover, the use of a reactive base like sodium hydride on an industrial scale is hazardous and operationally not user-friendly due to its pyrophoric and reactive nature.
PCT application WO 03/101917 discloses a process for the preparation of the title phenyl carbamate compounds involving reaction of phenol compounds with an alkylamine4-nitrophenyl carbamate. The process disclosed in WO 03/101917 partially overcomes the deficiency posed by the use of isocyanates or carbamoyl halides reported in the prior art. However, the reaction requires harsh conditions and long reaction times. For example, in Example 3 of WO 03/101917, the reaction of 3-(1-dimethylaminoethyl)phenol and N-ethyl-N-methyl-4-nitrophenyl carbamate was carried out in dimethylsulfoxide (DMSO) in the presence of anhydrous potassium carbonate at 90-100° C. for 35-40 hours. In addition, the reaction conditions may not be suitable because heating the chiral intermediate (S)-3-(1-dimethylaminoethyl)phenol with a base for an extended period of time may cause racemization of the chiral centre.
It is therefore an object of this invention to provide a more industrially applicable process for the preparation of aminoalkyl phenyl carbamate compounds.
It is a further object of the invention to use less toxic substances, such as for example 1,1′-carbonyldiimidazole, in the formation of racemic and enantiomerically-enriched (R)-or (S)-Rivastigmine, and their pharmaceutically acceptable addition salts.
Further and other objects of the invention will become apparent to those skilled in the art when considering the following summary of the invention and the more detailed description of the embodiments of the invention described herein.